1. Field of the Invention
The invention relates generally to compositions useful for treating modulating an immune response, and more specifically to chimeric interleukin-4 (IL-4) and interleukin-9 (IL-9) muteins that act as antagonists of interleukin-4, interleukin-9, and interleukin-13 activity, and to methods of using such IL-4 and IL-9 chimeric antagonist muteins to modulate a cytokine-mediated response of a cell and to ameliorate a disorder associated with cytokine-mediated responsiveness.
2. Background Information
Interleukin-9 (IL-9), interleukin-4 (IL-4) and interleukin-13 (IL-13) are cytokines produced by activated T-cells upon antigen stimulation. Asthma is characterized by reversible airflow obstruction and airway hyper-responsiveness (AHR), associated with an infiltration of the bronchial mucosa with activated T-lymphocytes (T-cells), and eosinophils. These cells, along with resident airway mast cells, secrete a variety of cytokines and mediators that play a fundamental role in the pathogenesis of the disease (1,2).
A number of studies suggest that IL-9, as a mediator of Th2-dependent immune responses, has a role in asthma. Human linkage analysis showed an association between the IL-9 gene and elevated serum levels of IgE production and airway hyper-responsiveness (3,4). IL-9 transgenic mice exhibit many characteristics of human asthma, and have a strikingly robust peribronchial and perivascular eosinophilia after allergen challenge. The eosinophilia was coincident with the up-regulation in lung epithelial cells of eotaxin, MIP-1 and MCP-1, MCP-3, and MCP-5, which are chemotactic for eosinophils (5). Other evidence for the role of IL-9 in asthma includes studies of the ability of IL-9 to stimulate mucin secretion by airway epithelial cells (6). Taken together, these studies illustrate and support the role of IL-9 in regulating many clinical hallmarks of asthma and allergic inflammation.
IL-4 and IL-13 are considered pivotal to the development of allergic inflammation and asthma. Studies conducted with animals deficient in either cytokine, or employing reagents that neutralize either IL-4 or IL-13 function, have elucidated the important role these cytokines play in regulating the primary and secondary immune response leading to airway inflammation and airway hyper-responsiveness (7,8). Cumulatively, these data suggest that IL-4 and IL-13 have overlapping as well as independent roles in the allergic airways response.
Decreased IL-9, IL-4, and IL-13 activity can decrease Th2 polarization of the T-cell response, decrease eosinophil survival and neutrophil activity, and attenuate mucus production by airway epithelial cells. These effects, in turn, can reduce airway hyper-reactivity and remodeling, while increasing gas exchange and clearance, and, therefore, can provide an effective therapeutic modality for several lung diseases, including, for example, asthma, chronic obstructive pulmonary disease (emphysema and chronic bronchitis), and related pulmonary conditions. As such, targeting of IL-9, IL-4, and IL-13 can provide a significant therapeutic benefit as compared to the targeting any of these cytokine, alone. Thus, a need exists for compositions that can modulate the effect of IL-9, IL-4, and IL-13 on cells.